Obesity, generally defined as a body mass index (BMI) of more than 30 kilogram per square meter (Kg/m2), is a major health problem throughout the world. It is a risk factor for hypertension, diabetes and cardiovascular disease. Obesity is viewed as an energy storage disorder, resulting when energy input exceeds energy output. Most of the excess calories are stored as fat (more than 95% of fat is triglyceride) in the adipose tissue leading to obesity, and when stored in non-adipose tissue it leads to insulin resistance. Hence, inhibition of triglyceride synthesis represents a potential therapeutic strategy for human obesity and type 2 diabetes.
Metabolic syndrome, also known as Syndrome-X, is characterized by increased body weight, altered glucose homeostasis with insulin resistance, elevated plasma triglyceride levels and low-density lipoprotein-cholesterol, high blood pressure, and increased risk of cardiovascular morbidity and mortality. The prevalence of metabolic syndrome has risen dramatically in the US and rest of the world. In the US, metabolic syndrome affects roughly 25% of adults over the age of 20 years and up to 45% of the population over the age of 50 years (JAMA, 287, 356-359 (2002)). The currently available therapies for addressing the disorders associated with metabolic syndrome are far from satisfactory.
A key enzyme in the synthesis of triglycerides is acylCoA:diacylglycerol acyltransferase (DGAT). Genes for two DGAT enzymes, DGAT-1 and DGAT-2 have been identified. Both DGAT-1 and DGAT-2 are highly expressed in tissues that are active in triglyceride synthesis such as white adipose tissue (WAT), intestine, liver, skeletal muscle and mammary gland (Proc. Natl. Acad. Sciences U.S.A., 95, 13018-13023 (1998)); J. Biol. Chem., 276, 38870-38876 (2001)).
Studies in experimental animals suggest that inhibiting or reducing the activity of the DGAT-1 enzyme results in resistance to the development of obesity, diabetes and associated complications. DGAT-1 knockout studies in mice have shown that these mice are viable and resistant to obesity (Nat. Genet., 25, 87-90 (2000)), whereas DGAT-2 knockout mice die soon after birth as there is no stored form of energy source due to lack of adipose tissues (J. Biol. Chem., 279, 11767-11776 (2004)). In contrast to DGAT-2 knockout mice, DGAT-1 knockout mice are viable and are resistant to diet-induced obesity and steatosis. In addition, these mice are more sensitive to insulin and leptin (J. Clin. Invest., 109, 1049-1055 (2002)). Heterozygous DGAT-1 knockout mice are also resistant to obesity (Thromb. Vasc. Biol., 25, 482-486 (2005)); Nutr. Metab (Lond.), 3, 10 (2006)). These studies together suggest that DGAT-2 plays a fundamental role in triglyceride synthesis and is essential for survival, whereas DGAT-1 contributes to triglyceride synthesis and plays an important role in regulating energy metabolism.
Additional studies with DGAT-1 antisense oligonucleotides indicate that inhibition of DGAT-1 results in decrease in blood glucose in ob/ob mice. Thus, resistance to obesity due to increased energy expenditure and reduced energy absorption along with an apparent improvement in insulin sensitivity associated with DGAT-1 deficiency suggests that inhibition of DGAT-1 could be a potential treatment strategy for addressing metabolic syndrome.
One target that has received much attention for treatment of metabolic syndrome is the DGAT-1 enzyme (Trends Cardiovasc. Medicine, 10, 188-192 (2000)); Curr. Drug Targets Immune Endocr. Metabol. Disorders, 3, 263-270 (2003)).
DGAT-1 inhibitors may also find use in the treatment of Hepatitis C infection Nature Medicine (10 Oct. 2010)
The following patent publications describe compounds that inhibit DGAT-1 activity:
WO2004/100881 and WO2006/044775 describe biphenyl-4-yl-carbonyl amino acid derivatives, WO2006/019020 describes substituted ureas, WO2006/134317 describes oxadiazole derivatives, WO2006/019020 describes substituted ureas, WO2009/071483 describes indazol-5-yl-ureas, WO2006/113919 and US 2004/0224997 describe aryl alkyl acid, and JP2004-67635 describes thiazoleamido substituted phenyl compounds.
WO 2007/087429 describes phenyl and pyridyl compounds for inflammation and immune related uses.
WO 2008/154601 describes compounds, composition and methods for treating viral infections mediated by virus in the Flaviviridae family of viruses.